Pig tissues offer stem cell hope

Monday

University of Missouri researchers have become some of the first in the world to transform connective tissue cells from a pig into stem cells capable of becoming any part of the anatomy.

The achievement, published in the scientific journal PNAS, comes within weeks of two separate Chinese research groups publishing similar findings on pig stem cells. This flurry of discoveries mark the first steps in what will likely be a long road of trial and error needed to produce a safe, effective method to induce adult pig cells to become stem cells that can be used to grow or repair organs.

The method used by the MU researchers was to remove the connective tissue cells, known as fibroblasts, from a pig fetus and transfer them to a controlled medium. Researchers then used a specially designed retrovirus to insert four “reprogramming” genes into the cells’ DNA. These four genes reprogrammed the cells to behave like stem cells. The cells then continued to reproduce at a normal rate, and a small percentage of them exhibited the attributes of stem cells, including the presence of the protein OCT4, a key marker for “undifferentiated cells.”

The key attribute of these stem cells and what gets scientists most excited is that they are “pluripotent,” meaning they are capable of differentiating into any of the 250 types of cells — nerve, heart or muscle — found in an adult pig. These stem cells are nearly identical to those found in embryos, which later differentiate inside the mother’s womb to become different parts of the body.

But R. Michael Roberts, an MU curator’s professor of animal science and biochemistry and one of the co-authors of the research, downplayed the significance of what his team has done. He said the important work is yet to come.

“There was nothing, basically, really innovative about the approach,” said Roberts, who said the real breakthrough occurred three years ago when two Japanese researchers discovered that reprogramming of fibroblasts was possible. “That was a bombshell,” he said.

The key advance by the MU researchers was applying this reprogramming method to the pig, a complex animal genetically similar to humans.

“This is a major step forward,” said Randall Prather of the MU Division of Animal Sciences, who has done research on adult pig stem cells. “Pigs are often the species of choice to use to study what might happen in humans. A prime example is cardiovascular disease. The other species that are often used for research just don’t mimic the human system the way a pig does.”

Pigs, Prather said, are about three times closer to a human than the mouse, which has been the focus of much of the research to this point. Pigs might someday serve as hosts producing tissue and organ transplants for humans, Prather said.

But Roberts said there is much work to be done before that can be considered. The next step will be figuring out a way to remove the four reprogramming genes after they’ve done their jobs. These genes continue to express themselves as the stem cells divide, and their existence might prevent proper cell differentiation.

“Ultimately, we’re going to have to go back and do this without using retroviruses or using retroviruses and then coming back and clipping them out,” Roberts said. The job of developing a vector that can remove these genes will be the job of Toshihiko Ezashi, a research assistant professor of animal sciences at MU and lead author on the study.

But despite the many unknowns, there are two main reasons the research is noteworthy. First, the cells are not harvested from embryos and do not involve cloning, so the research avoids ethical questions related to such stem cell use. And second, because the connective tissue cells could be taken from a patient, reprogrammed, differentiated into a new type of tissue and then grafted back into the same patient, it makes it much less likely that the patient’s body would reject the new tissue. It would be like getting a transplant from yourself.

But there is still a long road before any of that happens, Roberts said.

“Everybody is talking about stem cells, saying, ‘They’re wonderful; they’re going to be used for tissue regeneration; they’re going to be used to graft this and that,’ ” he said. “But you’d be crazy to do this” on humans “until you know the safety risks.”

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